BRCA1 haploinsufficiency for replication stress suppression in primary cells

Shailja Pathania, Sangeeta Bade, Morwenna Le Guillou, Karly Burke, Rachel Reed, Christian Bowman-Colin, Ying Su, David T. Ting, Kornelia Polyak, Andrea Richardson, Jean Feunteun, Judy E. Garber, David M. Livingston

Research output: Contribution to journalArticle

Abstract

BRCA1 - a breast and ovarian cancer suppressor gene - promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed 'conditional' haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.

Original languageEnglish (US)
Article number5496
JournalNature Communications
Volume5
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Haploinsufficiency
Repair
retarding
Defects
forks
cancer
Homologous Recombination
Satellite RNAs
Genes
cells
breast
strands
defects
Breast
Spindle Poles
Fibroblasts
Breast Neoplasms
suppressors
pathogenesis
Centrosome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Pathania, S., Bade, S., Le Guillou, M., Burke, K., Reed, R., Bowman-Colin, C., ... Livingston, D. M. (2015). BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nature Communications, 5, [5496]. https://doi.org/10.1038/ncomms6496

BRCA1 haploinsufficiency for replication stress suppression in primary cells. / Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna; Burke, Karly; Reed, Rachel; Bowman-Colin, Christian; Su, Ying; Ting, David T.; Polyak, Kornelia; Richardson, Andrea; Feunteun, Jean; Garber, Judy E.; Livingston, David M.

In: Nature Communications, Vol. 5, 5496, 2015.

Research output: Contribution to journalArticle

Pathania, S, Bade, S, Le Guillou, M, Burke, K, Reed, R, Bowman-Colin, C, Su, Y, Ting, DT, Polyak, K, Richardson, A, Feunteun, J, Garber, JE & Livingston, DM 2015, 'BRCA1 haploinsufficiency for replication stress suppression in primary cells', Nature Communications, vol. 5, 5496. https://doi.org/10.1038/ncomms6496
Pathania S, Bade S, Le Guillou M, Burke K, Reed R, Bowman-Colin C et al. BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nature Communications. 2015;5. 5496. https://doi.org/10.1038/ncomms6496
Pathania, Shailja ; Bade, Sangeeta ; Le Guillou, Morwenna ; Burke, Karly ; Reed, Rachel ; Bowman-Colin, Christian ; Su, Ying ; Ting, David T. ; Polyak, Kornelia ; Richardson, Andrea ; Feunteun, Jean ; Garber, Judy E. ; Livingston, David M. / BRCA1 haploinsufficiency for replication stress suppression in primary cells. In: Nature Communications. 2015 ; Vol. 5.
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